A major goal of translational pain research is to develop novel analgesic strategies that retain efficacy and do not pose unnecessary harm or discomfort to the patient being treated. However opioid drugs, such as morphine, remain the gold-standard for clinical pain relief but are severely limited by several detrimental sides effect including dependence, tolerance, and in select cases, a paradoxical pain state referred to as opioid- induced hyperalgesia (OIH). After millennia of documented opioid use, the specific neural circuits and synaptic mechanisms underlying the generation of analgesic tolerance and OIH are still disputed, and minimal gains have been made to improve opioid efficacy and safety. Opioid analgesia is produced via stimulation of mu opioid receptors (MORs) expressed along the nociceptive neural circuits, including TRPV1+ primary afferent nociceptors and numerous neurons in spinal cord and brain. The extent to which each of these MOR+ neuronal populations contributes to opioid analgesia, tolerance and OIH is currently not known, preventing the development of novel therapeutics to ameliorate opioid-based pain management. Prior electrophysiological studies found that brief opioid exposure is sufficient to generate long-term potentiation (LTP) between peripheral nociceptors and spinal cord neurons, signifying that this synapse might be a key neuronal substrate for morphine tolerance and OIH. The synaptic origin of opioid-induced LTP is presently unclear. Interestingly, previous studies indicated that ablation of TRPV1+ sensory neurons alone is sufficient to attenuate the development of morphine analgesic tolerance, OIH, and spinal LTP induction, suggesting that chronic opioid dosing may facilitate maladaptive plasticity in peripheral nociceptors that limit analgesic action. To further expand on this observation, we generated a conditional MOR knockout mouse line where MORs are absent in TRPV1+ afferents (MORTRPV1cKO), but intact in the spinal cord and brain. Strikingly, preliminary behavioral pharmacology studies show normal morphine analgesia but near total abrogation of tolerance and OIH. Here I propose to use an innovative combination of mouse genetics, optogentic-guided electrophysiology and behavioral pharmacology to test my central hypothesis that MORs in TRPV1+ nociceptors initiate the maladaptive plasticity underlying morphine analgesic tolerance and OIH. First, using light-assisted electrophysiological recordings in MORTRPV1cKO mice I will rigorously evaluate the effect of chronic morphine on synaptic transmission in peripheral afferent subpopulations. As a translational compliment study, I will test whether pharmacological blockade of MOR signaling in primary afferents is sufficient to abrogate morphine analgesic tolerance, OIH, and maladaptive synaptic plasticity. The cutting-edge methods and results obtained from these studies are expected to broadly impact our understanding of the neural circuits underlying morphine pathological sensory consequences and aim to develop novel therapeutic strategies to bolster opioid efficacy while minimizing side-effects.